The DB-ALM Project

Rationale of the DB-ALM

The European Commission's Joint Research Centre has established the DB-ALM based on a legal requirement1,2. It was recognised that the readily access to suitable and adequately described (non-animal) methods is a prerequisite for their use within decision making processes by regulators for safety assessments or by any end-user in biomedical sciences.

The DB-ALM is a public service and available in its current form since October 2006 launched in occasion of the 15th anniversary of ECVAM, today the EU Reference Laboratory on Alternatives to Animal Testing (EURL ECVAM). The first version of an entirely revised DB-ALM was released in 2014 and completed in September 2016.

The initial establishment of the service was supervised by an international Advisory Board that included representatives of academia and independent National competence centres for alternative methods. The further progress has been monitored by the EURL ECVAM Scientific Advisory Committee (ESAC).

The DB-ALM provides ready-to-use information presented as evaluated data-sheets in the form of summary records and/or detailed information on various aspects of animal alternatives in the field of biomedical sciences and toxicology for research and regulatory purposes. The data sheets are compiled by experts in the field with current focus on non-animal methods for toxicological evaluations of chemicals and formulations, but not restricted to these applications only. Method descriptions can cover various approaches: mathematical models, cell and tissue culturing techniques, testing strategies and advanced in vitro methods for safety and efficacy testing of chemical and medicinal products. The target user groups are the Interational and National Authorities, Industry, Academia, the Animal Welfare Movement and the services of the European Commission.

The DB-ALM is indicated by the European Chemicals Agency as a useful source of information on in vitro methods for REACH registration purposes (REgistration, Authorisation and restriction of CHemicals, EC Regulation No. 1907/2006), which can be considered during information gap analysis or in a weight of evidence approach:

In December 2014, the OECD has adopted a Guidance Document n°211 for Describing Non-Guideline In Vitro Test Methods to facilitate their consideration in regulatory applications. Herein the DB-ALM is indicated as one of the publicly available repository/library of methods that may be helpful in dissemination of comprehensive method descriptions. The format of the Method Summary in DB-ALM is adopted accordingly to ensure the compliance with the new guidance for new or updated data sheets entered after January 2015.

The Data Content

Origin of information

The DB-ALM provides full method descriptions and related information on alternative approaches to animal experimentation in form of evaluated data sheets. The information originates from:

EURL ECVAM validation activities

Individual submissions of methods at all stages of development by developers and/or users

After the selection, evaluation and final assessment of the available information, which is summarised, brought into a logical context and finally compiled into comprehensive ready-for-use data sheet(s). Further details of this process are provided in the Workstrategy section.

Topic areas

The initial focus has been given to in vitro techniques for toxicology assessments of chemicals and/or formulations for regulatory purposes, however DB-ALM also includes descriptions of computational and experimental approaches used in:

biokinetic analysis and exploratory or mechanistic studies of bioactive substances, chemicals and pharmaceuticals

the assessment of biocompatibility of medical devices

quality control and batch release testing of pharmaceuticals and vaccines

reduction and refinement of in vivo methods

Data sectors

The DB-ALM uses in-house (EURL ECVAM and other DG JRC services) competence and expertise in support to the definition and/or revision of the information content and collaborates with international experts in the respective fields of science for the definition of the individual data sheets addressing:

Topic Summaries

Thematic Reviews are made available (particularly during past activities) to provide an overall view about the information content on alternative and advanced methods available from the DB-ALM for an entire topic area (e.g. Percutaneous Absorption or Effects on Reproduction). The date of the last update is always indicated.

In Vitro / Advanced Approaches

Methods

Information on methods is provided at two levels of detail: summary descriptions or protocols:

Summary descriptions

The method summaries review the objectives and applications of a method, the scientific principle, its origin and need for it, the rationale for its experimental design, the status of development, validation or regulatory acceptance (as applicable). An example of a data reporting format provided in a synthesised manner for a non-animal Method Summary description laying down the criteria for data content is shown below. In 2015 it has been adapted to be compliant with the OECD Guidance Document n°211 for Describing Non-Guideline In Vitro Test Methods.

Extract of the Method Summary reporting format

METHOD NAME

One-two sentence abstract on the scientific principle of the method

GENERAL INFORMATION

Status

The extent of method's use by laboratories, development and eventual validation status according to internationally recognised principles, regulatory acceptance and standards.

Contacts

People and organisations familiar with the method (developers or expert users)

Practicalities

Proprietary or confidentiality issues, throughput, or special resources.

The origin and need for the method. The scientific principle and mechanistic or biological basis and relevance.

Procedure description

Where applicable, a short summary of the study design and the basic procedures, e.g. the preparations, dosing, exposure, sampling and measurements.

- Biological endpoint and measurement

- Endpoint value

- Test system

- Exposure regime

Quality and acceptance criteria

List of criteria ensuring the appropriate and adequate execution of the method (including controls and performance standards).

Data analysis and interpretation

Calculations and statistical methods used for data analysis and interpretation. The rules for the prediction of the in vivo effects from the data (if applicable).

METHOD PERFORMANCE

Robustness and applicability

Any performance measure most appropriate for the specific method, such as information on:

- reliability (within- and between-laboratory reproducibility)

- relevance (sensitivity, specificity and accuracy)

- accessibility of its results (where appropriate)

Possible applicability domains: test materials to which this method can/has been applied and proven compatible or incompatible with.

Discussion

Main advantages and/or limitations of the method, comparison to other related methods, possible adaptations/modifications, challenges, ethical concerns and potential for future developments.

NOTE:

The sections are not mandatory. The information provided depends on the type of the method (e.g. experimental methods are realised differently than computational ones), its intended use and development status.

In the DB-ALM the term "method" is simultaneously used for: approaches, techniques, assays, experimental or computational models.

Protocols

More technical information is provided to such a detail that allows the transfer of a method to a laboratory in the form of a standard operating procedure. The data entry format for Protocols accommodates all technical details necessary to adopt the method in a new laboratory without the need of additional information.The initial protocol collection has originally been established under the name INVITTOX by the Fund for the Replacement of Animals in Medical Experiments (FRAME, UK) and has been transferred to and further developed and expanded by the EURL ECVAM since 1996.

Projects and Studies

Evaluation Studies

Information is provided on studies conducted to establish the methods/assays/test systems and to assess the methods’ variability and robustness over time. Data sheets are based on the information available from the literature and are made available as summary records covering the objective, procedure and outcome.

EU Integrated Projects

Information is provided on studies conducted by selected EU-funded research consortia with the aim to develop new 3R's (replacement, reduction and refinement) test methods and strategies in safety testing, where no alternatives to the use of animals are currently available.

Formal Validation Studies

Data sheets are based on the outcome of the selected formal validation studies for 5 topic areas. The study is considered "formal" if done according to EURL ECVAM's modular approach to test development and validation. This sector contains summary records on studies assessing the reproducibility within and between laboratories and over time (reliability) and the usefulness (relevance) of the method with relevance to the animal alternatives topic area.

Compounds

This sector contains the description of selected investigations and respective results for a substance with a given method carried out by various laboratories. Test Results data sheets include information on type of tested material, names of the laboratories where the experiment took place, experimental details, such as dosage and exposure regime, information on data interpretation and source references.

People & Institutions Active in the Field of Alternative Methods (Who is Who)

The inventory of people and institutions active in the field of animal alternatives, provided on voluntary basis. This includes:

Contact details of scientists and institutions using/developing/evaluating specific in vitro techniques that are available as DB-ALM protocols or are originating from voluntary manifestations of interest resulting among others from a survey conducted by the EURL ECVAM

Institution profile

Fields of activity

Bibliographic References

procedures independently of having them included in the individual data sheets.

Scientific Terminology and database classifications

Data compilation and retrieval procedures in the DB-ALM are based on the classification lists and controlled vocabularies maintained in-house, that cover:

Experimental systems refer to the (bio)systems used to study the investigated effect

Topic areas refer to the field of applications of the methods

Categories of methods/models according to the level of biological organisation

Information retrieval

The DB-ALM provides users oriented information in the form of evaluated data sheets with the different levels of information content, but also different possibilities of information retrieval are offered: free text search, and guided search options. The DB-ALM information content is organised in a semi-structured manner and is classified based on its contents and concepts (e.g. topic concerned, level of assessments, category of model used including its level of biological organisation, biological endpoints and their measurements, status of development, or regulatory acceptance). Controlled vocabularies are used during the description of the methods to better reflect and consequently retrieve the information contained, a fundamental principle of today's scientific knowledge management.

The so called "faceted navigation" could consequently be applied to the DB-ALM allowing users to explore the collections of information and concepts from different points of view and to navigate the information along multiple paths with its individual search options in a more user friendly manner.

The DB-ALM revised version provides a refined data retrieval approach for the "method data sector" first offering a choice between two search strategies implemented with state-of-the-art search technology:

Free text search option

If no search terms or filters are used: the complete content of the "Methods" data sector will be displayed as an alphabetical list according to their fields of application with the choice of ordering by:

biological endpoints assessed or

the names of the method

Search filters can be applied by typing search terms, wildcards (*, %) and logical operators (e.g. AND, OR, NOT). When the first word or letters are being typed into the free text search field, the auto-complete function is activated and suggests selected terms found in specific database records where the matching keyword might be particularly relevant, due to its presence in the: topic, method name, biological endpoint or experimental model, contact or compounds field or contained in any other database classification list. The user is, therefore, offered a choice between either continuing his or her intended data retrieval procedure, or selecting a search term from the list of suggestions.

Guided search option

In contrast to the free text search option, the guided search offers modular interfaces that allow the user to add/remove search fields at any time of the data retrieval procedure. Using this progressive incremental query construction, users are able to formulate the equivalent of a sophisticated query by taking a series of small, simple steps. Also in this case, the auto-complete function can be used with the assistance of controlled vocabularies or freely chosen search terms can be entered by using wild cards and Boolean operators.

The following search fields (parameters) are available and can be used in any combination:

Method Names

Topics

Models & Strategies

Status

Biological Endpoints and Measurements

Experimental Systems

Terms from the classification lists: Topics, Models & Strategies and Status can be selected from a pre-defined drop-down list allowing for one or more terms to be combined. Queries including the Biological Endpoints and Measurements, Experimental Systems and Method Names are aided by the auto-complete function offering a choice of matching database records. When ignored and no search term is entered, the complete list of the database classification terms for the selected search parameter will be searched and linked data sheets retrieved.

Display of search results

Regardless of the search strategy used, the search results are displayed as an alphabetically-sorted list of the fields of application, including: the name/title, abstract, the link to the full data sheet (available as pdf document) and the links to the related database contents to the methods:

Topic Summaries

Projects and Studies

Evaluation studies

EU integrated projects

Validation Studies

Compounds and test results

People and institutions active in the field of alternative methods/Methods contact

Bibliography

The Search Results display provides now more options on how the results are displayed:

Results can be filtered on Methods or Protocols or both

Results can be sorted by:

topic area

biological endpoint

experimental system used

area of concern, such as chemicals with different uses, vaccines etc.

Status of development, validation or regulatory acceptance

Method name

1 SEC(91)1794, Communication of the European Commission to Council and the European Parliament in October 1991, pointing to a requirement in Directive 86/609/EEC on the protection of animals used for experimental and other scientific purposes, OJ L No. 358, 18.12.1986.

2 Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes, Article 48, Annex VII (2)(d), OJ L Nr. 276/33, 20.10.2010.